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Original Investigation
October 12, 2020

Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring

Author Affiliations
  • 1Department of Anesthesiology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 2Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena
  • 3Department of Internal Medicine, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 4Department of Pediatrics, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 5Department of Obstetrics & Gynecology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 6Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina
JAMA Pediatr. Published online October 12, 2020. doi:10.1001/jamapediatrics.2020.3231
Key Points

Question  Is there an association between maternal labor epidural analgesia given for vaginal delivery and risk of autism spectrum disorders in children?

Findings  In this multiethnic population-based clinical birth cohort that included 147 895 children, autism spectrum disorders were diagnosed in 1.9% of the children delivered vaginally with epidural analgesia vs 1.3% of the children delivered vaginally without the exposure, a 37% relative increase in risk that was significant after adjusting for potential confounders.

Meaning  This study suggests that exposure to epidural analgesia for vaginal delivery may be associated with increased risk of autism in children; further research is warranted to confirm the study findings and understand the potential mechanisms.

Abstract

Importance  Although the safety of labor epidural analgesia (LEA) for neonates has been well documented, the long-term health effects of LEA on offspring remain to be investigated.

Objective  To assess the association between maternal LEA exposure and risk of autism spectrum disorders (ASDs) in offspring.

Design, Setting, and Participants  Data for this retrospective longitudinal birth cohort study were derived from electronic medical records from a population-based clinical birth cohort. A total of 147 895 singleton children delivered vaginally between January 1, 2008, and December 31, 2015, in a single integrated health care system were included. Children were followed up from the age of 1 year until the first date of the following occurrences: clinical diagnosis of ASD, last date of health plan enrollment, death, or the study end date of December 31, 2018.

Exposures  Use and duration of LEA.

Main Outcomes and Measures  The main outcome was clinical diagnosis of ASD. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of ASD associated with LEA exposure.

Results  Among the cohort of 147 895 singleton children (74 425 boys [50.3%]; mean [SD] gestational age at delivery, 38.9 [1.5] weeks), 109 719 (74.2%) were exposed to maternal LEA. Fever during labor was observed in 13 055 mothers (11.9%) in the LEA group and 510 of 38 176 mothers (1.3%) in the non-LEA group. Autism spectrum disorders were diagnosed in 2039 children (1.9%) in the LEA group and 485 children (1.3%) in the non-LEA group. After adjusting for potential confounders, including birth year, medical center, maternal age at delivery, parity, race/ethnicity, educational level, household income, history of comorbidity, diabetes during pregnancy, smoking during pregnancy, preeclampsia or eclampsia, prepregnancy body mass index, gestational weight gain, gestational age at delivery, and birth weight, the HR associated with LEA vs non-LEA exposure was 1.37 (95% CI, 1.23-1.53). Relative to the unexposed group, the adjusted HR associated with LEA exposure of less than 4 hours was 1.33 (95% CI, 1.17-1.53), with LEA exposure of 4 to 8 hours was 1.35 (95% CI, 1.20-1.53), and with LEA exposure of more than 8 hours was 1.46 (95% CI, 1.27-1.69). Within the LEA group, there was a significant trend of ASD risk associated with increasing duration of LEA exposure after adjusting for covariates (HR for linear trend, 1.05 [95% CI, 1.01-1.09] per 4 hours). Adding fever to the model did not change the HR estimate associated with LEA exposure (adjusted HR for LEA vs non-LEA, 1.37 [95% CI, 1.22-1.53]).

Conclusions and Relevance  This study suggests that maternal LEA may be associated with increased ASD risk in children. The risk appears to not be directly associated with epidural-related maternal fever.

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    3 Comments for this article
    Study Design Concerns
    Kai Rabenstein, MB, BCh, BAO, MD | East Sussex Healthcare Trust, UK

    As far as I can make out, the authors of this study were attempting to control for a large number of potential confounders (the abstract mentions 15 geographic, socioeconomic and biological factors) but failed to consider the 2 most intuitively obvious: maternal (i.e. epidural decision maker's) diagnosis of ASD and family history on both parental sides. It is very well established that the genetic/heritable component in autism is very strong. This oversight renders the study findings questionable.

    CONFLICT OF INTEREST: I have an (adult) diagnosis of Asperger's and advocate for the recognition of neurodivergence among the medical profession
    Confounding Labor Variables
    Brooke Orosz, PhD |
    It is well established that labor complications and fetal distress can cause brain injury. In addition, women having long and difficult labors are more likely to request epidural anesthesia. The study authors did not look at lengh of labor, duration of ROM, incidence of fetal distress or emergency cesarean, Apgar scores, or other labor-related variables.

    If perinatal rather than genetic factors really do play a significant  role in autism, difficult labor is a much more plausible mechanism than the tiny traces of epidural drugs that enter the bloodstream and pass to the baby.
    CONFLICT OF INTEREST: None Reported
    Yes, There Are Likely Unmeasured Confounders
    B Segal, MD, MHCM | Wake Forest School of Medicine
    I agree with Dr. Rabenstein that there may be unmeasured confounders, and this study must be viewed as hypothesis-generating. One approach in ASD studies with other associations to try to control for parental genetics has been to use sibling controls. I think that approach would be useful in exploring this association further as well.
    CONFLICT OF INTEREST: Coauthor on the study in question
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